Sphingomyelin (SM) can be converted into ceramide (Cer) by neutral sphingomyelinase (NSM) and acid sphingomyelinase (ASM). Cer is a second messenger of lipids and can regulate cell growth and apoptosis. Increasing evidence shows that NSM and ASM play key roles in many processes, such as apoptosis, immune function and inflammation. Therefore, NSM and ASM have broad prospects in clinical treatments, especially in cancer, cardiovascular diseases (such as atherosclerosis), nervous system diseases (such as Alzheimer's disease), respiratory diseases (such as chronic obstructive pulmonary disease) and the phenotype of dwarfisms in adolescents, playing a complex regulatory role. This review focuses on the physiological functions of NSM and ASM and summarizes their roles in certain diseases and their potential applications in therapy.